Milrinone Versus Dobutamine in Critically Ill Patients

Acute Coronary Syndrome Clinical Trial

Official title:

Comparison of Milrinone Versus Dobutamine in a Heterogeneous Population of Critically Ill Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03207165
• Other study ID #: 20160975-01H
• Status: Completed
• Phase: Phase 4
• Start date: August 30, 2017
• Est. completion date: June 12, 2020

Study information

• Verified date: June 2020
• Source: Ottawa Heart Institute Research Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators are interested in determining if there is a meaningful difference between two of the most commonly used medications used to improve the pumping function of the heart among critically ill patients admitted to the Coronary Care Unit (CCU) at the University of Ottawa Heart Institute (UOHI). To do this, the investigators will randomly assign patients who are felt to require use of these medications by their treating physicians to one of the two most commonly used agents in Canada: Milrinone or Dobutamine. Each patient will be closely monitored by their healthcare team, and their medication will be adjusted based on each patient's clinical status. Information from blood work (e.g. kidney and liver function, complete blood counts, and other markers of how effectively blood is circulating in the body), assessment of end-organ function (e.g. urine output, mentation), abnormal heart rhythms noted on monitoring and results of imaging studies (e.g. angiogram, echocardiograms.) will be collected for analysis. All patients will be followed for the duration of their hospital stay at UOHI.

Description:

The use of various inotropes in the care of critically ill cardiac patients has become increasingly widespread: while predominantly used in decompensated heart failure, they have also been used in cardiogenic shock complicating acute coronary syndrome (ACS) and septic shock. Purported mechanisms of efficacy include improved cardiac output, improved end-organ perfusion, and vasodilation of both pulmonary and systemic circulations. Two of the most commonly used agents are Milrinone, a phosphodiesterase 3 inhibitor, and Dobutamine, a synthetic catecholamine with affinity for both beta-1 and 2 receptors. Both the American College of Cardiology (ACC) and the European Society of Cardiology (ESC) support inotropes for acute and chronic heart failure management with low cardiac output states. Furthermore, the ACC recommends consideration of inotropic therapy within the STEMI guidelines when ACS is complicated by cardiogenic shock, heart failure or for hemodynamic support in isolated right ventricle infarctions. Beyond primarily cardiac etiologies, inotropes have been identified as first-line additive therapy for cardiac augmentation to Norepinephrine in patients with septic shock complicated by myocardial dysfunction. Despite the lack of convincing data supporting a morbidity or mortality benefit with the use of inotropes in severe, decompensated heart failure, cardiogenic or septic shock, or in ACS, inotropic therapy is still widely used across various critical care settings. Furthermore, to date, there has been no head to head comparison of the two more commonly used positive inotropes: Dobutamine and Milrinone. Selection of one inotrope over another is often guided by physician and center preference, and consideration of and purported avoidance of possible adverse effects. In this pilot study, the investigators aim to describe that characteristics of patients receiving inotropic support in the CCU setting and identify possible differences in morbidity and mortality between Dobutamine and Milrinone among a heterogeneous population of patients admitted to the CCU at UOHI, which may help to inform a larger clinical trial in the future.

The purpose of this pilot study is to: (a) describe the characteristics of patients receiving inotropic support in the coronary care unit (CCU) setting (hemodynamics prior to inotrope initiation, etiology of cardiogenic shock state, use of PA catheter and values if deemed necessary by medical team) and (b) identify possible differences in morbidity [atrial and ventricular arrhythmias, hepatic and renal function, markers of end-organ perfusion (lactate, urine output, mentation status), use of vasopressors, sustained hypotension of systolic blood pressure less than or equal to 90 mmHg for greater than 30 minutes, need for mechanical support, cardiac transplant, total length of CCU stay, length of CCU stay greater than 14 days] and mortality between patients in cardiogenic shock treated with Dobutamine versus Milrinone.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 192
• Est. completion date: June 12, 2020
• Est. primary completion date: June 12, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Have one or more of the following:

• Low cardiac output state, evidenced by sustained hypotension (systolic blood pressure <90 mmHg) and end organ dysfunction (altered level of consciousness, elevated lactate, renal or hepatic dysfunction)

• Clinical evidence of systemic and/or pulmonary congestion despite use of vasodilators and/or diuretics

• ACS complicated by cardiogenic shock (defined as persistent hypotension with systolic blood pressure <90 mmHg with severe reduction in cardiac index [<1.8 L/min/m2 without support or <2.2 L/min/m2 with support], left ventricular end-diastolic pressure >18 mmHg)

• Augmentation of cardiac output when patient already on maximal vasopressor therapy

• Or medical team's decision that patient needs inotropic therapy

Exclusion Criteria:

• Unwillingness or inability to provide informed consent by the patient or substitute decision maker for healthcare decisions

• Female participants who are currently pregnant

• Patients presenting with an out-of-hospital cardiac arrest (OOHCA)

• Healthcare team preference for use of specific inotrope (Milrinone or Dobutamine)

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Cardiac Output, Low
• Cardiogenic Shock
• Low Cardiac Output Syndrome
• Pulmonary Edema
• Shock, Cardiogenic
• Syndrome

Intervention

Drug:
• Milrinone
Patients will be initiated on Milrinone at 0.125 mcg/kg/min [stage 1] and will be titrated according to a blinded protocol from stages 2 to 5 [0.250, 0.375, 0.5 and >0.5 ug/kg/min]. All orders to initiate and titrate the dose of the allocated inotrope will be written in the chart as follows: 'Study inotrope dose to be [increased/decreased/maintained] at stage [1-5]' so as to ensure that treating physicians remain blinded to the allocated drug.
• Dobutamine
Patients will be initiated on Dobutamine at 2.5 mcg/kg/min [stage 1] and will be titrated according to a blinded protocol from stages 2 to 5 [5.0, 7.5, 10 and >10 ug/kg/min]. All orders to initiate and titrate the dose of the allocated inotrope will be written in the chart as follows: 'Study inotrope dose to be [increased/decreased/maintained] at stage [1-5]' so as to ensure that treating physicians remain blinded to the allocated drug.

Locations

Country	Name	City	State
Canada	University of Ottawa Heart Institute	Ottawa	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Ottawa Heart Institute Research Corporation

Country where clinical trial is conducted

Canada, 

References & Publications (5)

Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, Cheng ML, Wynne J; ADHERE Scientific Advisory Committee and Investigators; ADHERE Study Group. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005 Jul 5;46(1):57-64. — View Citation

Aranda JM Jr, Schofield RS, Pauly DF, Cleeton TS, Walker TC, Monroe VS Jr, Leach D, Lopez LM, Hill JA. Comparison of dobutamine versus milrinone therapy in hospitalized patients awaiting cardiac transplantation: a prospective, randomized trial. Am Heart J. 2003 Feb;145(2):324-9. — View Citation

Karlsberg RP, DeWood MA, DeMaria AN, Berk MR, Lasher KP. Comparative efficacy of short-term intravenous infusions of milrinone and dobutamine in acute congestive heart failure following acute myocardial infarction. Milrinone-Dobutamine Study Group. Clin Cardiol. 1996 Jan;19(1):21-30. — View Citation

King JB, Shah RU, Sainski-Nguyen A, Biskupiak J, Munger MA, Bress AP. Effect of Inpatient Dobutamine versus Milrinone on Out-of-Hospital Mortality in Patients with Acute Decompensated Heart Failure. Pharmacotherapy. 2017 Jun;37(6):662-672. doi: 10.1002/phar.1939. — View Citation

Yamani MH, Haji SA, Starling RC, Kelly L, Albert N, Knack DL, Young JB. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact. Am Heart J. 2001 Dec;142(6):998-1002. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Sustained hypotension of systolic BP	Sustained systolic blood pressure hypotension of less than or equal to 90 mmHg for greater than or equal to 30 minutes (or requiring medical intervention)	Through duration of hospitalization in CCU, up to 12 weeks following admission
Other	Atrial arrhythmias requiring medical intervention	Atrial flutter, fibrillation or tachycardia requiring medical intervention	Through duration of hospitalization in CCU, up to 12 weeks following admission
Other	Need for intravenous or oral anti-arrhythmic therapy	Initiation of intravenous or oral anti-arrhythmic therapy	Through duration of hospitalization in CCU, up to 12 weeks following admission
Other	Ventricular arrhythmias	Ventricular arrhythmias (monomorphic or polymorphic ventricular tachycardia [VT] greater than 30 seconds or hemodynamically unstable ventricular arrhythmia requiring intervention, or VF)	Through duration of hospitalization in CCU, up to 12 weeks following admission
Other	Need for up-titration or addition of new vasopressor therapy	Need for up-titration or addition of new vasopressor therapy	Through duration of hospitalization in CCU, up to 12 weeks following admission
Primary	Composite Primary End Point	Composite of all-cause in-hospital death, non-fatal MI, TIA or CVA diagnosed by a Neurologist, renal failure requiring renal replacement therapy, need for cardiac transplant or new mechanical support, any atrial or ventricular arrhythmia leading to cardiac arrest and resuscitation.	Through duration of hospitalization, up to 12 weeks following admission
Primary	All-cause in-hospital death	All-cause in-hospital death	Through duration of hospitalization, up to 12 weeks following admission
Primary	Non-fatal myocardial infarction [MI]	As defined by Thygesen et al., 2012 (Circulation)	Through duration of hospitalization, up to 12 weeks following admission
Primary	Transient ischemic attack [TIA] or cerebrovascular accident [CVA]	Transient ischemic attack or cerebrovascular accident as diagnosed by a Neurologist either clinically and/or radiographically	Through duration of hospitalization, up to 12 weeks following admission
Primary	Stay in CCU greater than or equal to 7 days	Stay in CCU greater than or equal to 7 days	Through duration of hospitalization, up to 12 weeks following admission
Primary	Acute kidney injury requiring renal replacement therapy	Acute kidney injury requiring renal replacement therapy (intermittent hemodialysis or continuous renal replacement therapy)	Through duration of hospitalization, up to 12 weeks following admission
Primary	Need for advanced mechanical support [specifically, intra-aortic balloon pump, Impella, ventricular assist device or extra-corporeal membrane oxygenation] or cardiac transplant	Need for new mechanical support or cardiac transplant	Through duration of hospitalization, up to 12 weeks following admission
Secondary	Time on inotropes	Total time on inotropes (in hours)	Through duration of hospitalization, up to 12 weeks following admission
Secondary	Non-invasive or invasive mechanical ventilation	Total number of days requiring non-invasive or invasive mechanical ventilation	Through duration of hospitalization, up to 12 weeks following admission
Secondary	Change in cardiac index ([CI]	Change in cardiac index measured with PA catheter	Through duration of hospitalization, up to 12 weeks following admission
Secondary	Change in pulmonary capillary wedge pressure [PCWP]	Change in pulmonary capillary wedge pressure measured with PA catheter	Through duration of hospitalization, up to 12 weeks following admission
Secondary	Change in pulmonary vascular resistance [PVR]	Change in pulmonary vascular resistance measured with PA catheter	Through duration of hospitalization, up to 12 weeks following admission
Secondary	Change in systemic vascular resistance [SVR]	Change in systemic vascular resistance measured with PA catheter	Through duration of hospitalization, up to 12 weeks following admission
Secondary	Presence of acute kidney injury	Presence of acute kidney injury (defined by KDIGO as creatinine increased by 26.5 umol/L, 1.5 times baseline within prior 7 days, or urine volume <0.5 mL/kg/hour for greater than or equal to 6 hours	Through duration of hospitalization, up to 12 weeks following admission
Secondary	Serum lactate	Normalization of serum lactate	Through duration of hospitalization, up to 12 weeks following admission
Secondary	Arrhythmia requiring medical team intervention	Arrhythmia requiring medical team intervention, either through electrical or chemical cardioversion or any intravenous anti-arrhythmia medication administration	Through duration of hospitalization, up to 12 weeks following admission